Paracetamol (n-acetyl-4-aminophenol) is an active ingredient that has been widely used in the last 4 decades in pharmaceutical preparations due to its activity as an analgesic and an antipyretic which was introduced by Von Mering in 1893. It is further well tolerated by human beings and does not alter the acid-base equilibrium, therefore it is widely used to relive pain both in adults and in children and in the elderly. A large number of pharmaceutical preparations to be administered orally or even topically are known. However, it is difficult to obtain a pharmaceutical preparation for injection and particularly, a ready-to-use solution for intravenous perfusion, due to the fact that paracetamol is not very soluble in water and its solutions in aqueous medium are unstable in the presence of oxygen and/or light, being decomposed through a plurality of degradation pathways which are well known and are described for example in the article “Stability of aqueous solutions of N-acetyl-p-aminophenol”, by K. T. Koshy and J. L. Lach, J. Pharmaceutical Sciences, Vol 50 (2) (February 1961), p. 113-118. This instability in aqueous medium is shown by the appearance of degradation substances causing a coloring in the solution. The different substances causing the coloring of the solution include benzoquinoimines which are hepatotoxic in humans.
However, the development of color in pharmaceutical solutions and especially in injectable formulations which must be completely transparent involves a serious problem, because the presence of said color is indicative of the existence of unwanted compounds in the formulation and therefore leads to the rejection of the injectable product without being used.
One of the causes of paracetamol degradation is based on chemical oxidation reactions in which the oxygen present in the solution is the main precursor of this degradation. The secondary cause of degradation may be the deacetylation of the amino group generating p-aminophenol which is also quickly degraded producing p-benzoquinoneimine. This deacetylation takes places both at acid pH and (much faster) at basic pH once the phenolate form is present.
In vivo, most of the paracetamol is metabolized through the formation of these phenolate form derivatives, mainly through the gluconated derivative and through the sulfonated derivative:

Obtaining stable paracetamol solutions in aqueous medium can be solved by means of several joint actions.
1) Establishing an optimal pH in which the formation of 4-aminophenol is prevented or minimized, as has been indicated by K. Thomas Koshy and Jon L. Lach in the previous indicated reference “Stability of aqueous solutions of N-acetyl-p-aminophenol”, J. of Phar. Sci., Vol 50 No. 2 (1961), 113-118, the hydrolysis of the acetate group of paracetamol is minimized between pH=4.5 and pH 6.0.
2) Preventing the presence of oxygen in solution. This action is described in Spanish patent no. 2,201,316, from the validation in Spain of European patent EP 858,329 B1, issued to Pharmatop SCR. This document discloses a process whereby paracetamol oxidation is prevented by means of eliminating the main element activating the reaction, oxygen, with nitrogen bubbling. By further keeping the solution in a completely hermetic bottle, the stability of paracetamol in solution is ensured for long time periods, with minimal impurity levels and the total absence of color in the solution. It must be deduced by the characteristics of the SCR Pharmatop product that its must be kept in suitable bottles preventing the incorporation of oxygen into the solution and therefore these solutions cannot be stored in individual oxygen-permeable bottles such as plastic materials.
The joint action on the two previous factors allows obtaining a stable paracetamol solution which does not develop color for a long time period.
International patent publication WO2004/071502 A1, issued to Nguyen-Xuan, describes a paracetamol formulation containing a buffer agent with a pKa between 4.5 and 6.5, an isotonic agent and a paracetamol dimer. The stability of paracetamol in solution is attributed to the presence of the paracetamol dimer of formula I produced in situ by treatment of the solution with a temperature between 100° C. and 130° C. for at least 5 minutes. This formulation does not need the elimination of oxygen and can be stored in some plastic materials. However, it has the following drawbacks:                1. Since it does not contain factors preventing the oxidation of paracetamol, polymerization impurities such as the mentioned dimer are generated over time, providing color to the solution and turning it into a product that is unsafe in its use because at the time of its use it is not possible to know if the color is from the formation of paracetamol polymers or benzoquinoneimines or of other substances with an unknown origin.        2. The stability of these solutions is reduced when they are stored in plastic materials such as PVC, the composition of which does not use antioxidants. In other words, they must be stored in plastic materials such as polypropylene, polyolefins, polyethylene, polyethylene vinyl acetate, containing antioxidants and preventing or making the entrance of oxygen into the solution difficult. These materials typically contain one of several of the following antioxidants:            1.—butylhydroxytoluene,    2.—Pentaerythrityl tetrakis(3,5-di-tert-butyl-4-hydroxyphenyl)propionate;    3.—1,3,5-tris(3,5-di-tert-butyl-4-hydroxybenzyl)-s-triazine-2,4,6(1H,3H,5H)-trione;    4.—octadecyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate;    5.—ethylenebis[3,3-bis[3-(1,1-dimethylethyl)-4-hydroxyphenyl]butanoate];    6.—dioctadecyl disulfide;    7.—2,2′,2′,6,6′,6″-hexa-tert-butyl-4,4′,4″-[(2,4,6-trimethyl-1,3,5-benzenetriyl)trismethylene]triphenol;    8.—2,2′-bis(octadecyloxy)-5,5′-spirobi[1,3,2-dioxaphosphinane];    9.—didodecyl 3,3′-thiodipropionate;    10.—dioctadecyl 3,3′-thiodipropionate;    11.—tris(2,4-di-tert-butylphenyl)phosphate;    12.—5 different substances containing the phenyl phosphinite group.    13.—Butylhydroxyanisole
Therefore, the problem to be solved by the present invention is to provide an alternative stable injectable paracetamol solution preventing the development of an unwanted color of the solution over time.
The solution to this problem is based on the fact that the authors have identified that when substances that can react with the p-acetyl aminophenolate form, an intermediate chemical species both in the degradation by deacetylation and in oxidation, these paracetamol degradation pathways are significantly reduced, a highly stable injectable paracetamol solution with a minimal content of impurities being obtained. The reason for this is that the formation of intermediate products such as gluconated or sulfonated derivatives with the phenolate form, although they can be unstable in solution, nevertheless significantly reduces paracetamol degradation. Sulfate, gluconate or furfural ions can be found in solution as byproducts generated by this degradation.
Therefore, aqueous paracetamol solutions for their use by perfusion of the invention comprise a substance that can react with phenolates turning them into their O-derivatives or coordination compounds. In a preferred embodiment of the invention, such agents are selected from the group consisting of reducing sugars such as glucose, galactose, fructose; the acid forms of these sugars or their salts, such as gluconate, glucuronate, glucoheptanoate, galactate; chemical species containing sulfur in an oxidation state less than +6, sodium formaldehyde sulfoxylate, sulfites or thiourea or any combination of the previous substances. These compositions produce a solution with very reduced levels of impurities and the absence of color in the solution for long time periods, being able to be stored in antioxidant-free plastic materials.
It is possible to find aqueous paracetamol formulations for perfusion containing antioxidants in the prior art. However, there is no known document studying the different antioxidant power of different substances through the reactivity of phenolate in aqueous solution or its possible practical consequences. The authors have now found that the action on this intermediate product in the paracetamol hydrolysis/oxidation process allows providing different degrees of protection of paracetamol against oxidation in the same pH conditions, such that it is possible to obtain a solution with the aforementioned advantages by suitable selecting the antioxidant or substance that can react with the intermediate phenolate form.
On the other hand, it is known that phenols can generate complexes with metal ions by means of their phenolate form, therefore this fact can also be used to prevent the occurrence of oxidized forms of paracetamol. The formation of metal complexes with phenolate ions can affect the end result for obtaining a stable and colorless paracetamol solution and it is necessary to consider this effect because although generally all of them case a bathochromic effect in the absorption of radiation of paracetamol, shifting the absorption towards more colored area of the spectrum, not all of them do so to the same extent: in the case of cations causing the formation of colored complexes with the phenolate form, as may be the case of iron or zinc, their presence must be prevented by means of adding a suitable chelating agent to the composition, whereas those cations producing colorless forms such as magnesium will favor the stability of the solution since they act as scavengers of the phenolate ions produced.
A very important factor to be considered is that an equilibrium must be achieved between solution color/impurities from paracetamol degradation and impurities from the degradation of the substances used as stabilizers: Although the prior art has described aqueous paracetamol solutions for perfusion comprising glucose as an isotonic agent, it is however necessary to use amounts of the order of 5% m/v to provide isotonicity to the solution, with which amounts a colored solution is obtained after a few months of its production, therefore these solutions would not be suitable in the present invention. It is therefore necessary to use the suitable amount for each stabilizing compound so that said compound shows its stabilizing effect without developing any substantial color over time.
A last factor to be taken into account is that the solubility of paracetamol in aqueous medium is of the order of 12 mg/ml at a temperature of 20° C. and 8 mg/ml at 4° C., such that the process or composition of the solution must prevent the crystallization of paracetamol. This effect is solved by means of filtering the solution through a pore size of 0.45 microns or less, or adding a solubilizing agent as described in international publication WO03033026 issued to BIOREN S. A., disclosing an aqueous paracetamol solution obtained by mixing paracetamol and propylene glycol in citrate medium at a pH comprised between 4.5 and 6.5 and heating said solution at a temperature between 70° C.-130° C.